Patients with end-stage renal disease (ESRD) are currently treated by kidney transplantation or by dialysis to detoxify the blood. Kidney transplantation involves the surgical replacement of the patient's kidney with a kidney from either a live donor or a cadaver. In order to avoid rejection of the transplanted organ, the recipient patient must receive life-long drug treatment to suppress immune rejection. Even then, the kidney may be rejected and will have to be removed. The patient then will require another transplantation or dialysis.
Treatment by dialysis is performed by either hemodialysis or peritoneal dialysis. In hemodialysis the patient's blood is channeled to a dialyzer which contains a synthetic semi-permeable membrane. Simultaneously, fresh dialysate from an external source is also channeled into the dialyzer where the blood and dialysate are separated by the semi-permeable membrane. The purified blood is then returned to the patient while the used dialysate is discarded. The process takes 3-4 hours and must be repeated three times a week. Hemodialysis performed in this manner is problematic in that normalization of the patient's fluid and electrolyte balance occurs rapidly during the intradialytic period, and then deteriorates during the interdialytic period. Also, the frequency and duration of dialytic treatment potentially curtail normal activities for the dialysis patient.
Attempts have been made to address these problems by performing dialysis continuously with a wearable device. U.S. Pat. No. 5,284,470, issued Feb. 8, 1994 to Beltz, describes a wearable, portable hemodialyzer. Murisasco et al. (1986) Trans. Am. Soc. Artif. Intern. Organs 32:567-571, disclose a wearable continuous hemofiltration device. Neff et al. (1979) Trans. Am. Soc. Artif. Intern. Organs 25:71-73 described a hemofiltration system attached to a patient's forearm. However, presently available hemodialysis systems require the administration of anticoagulants to the patient to prevent clotting of the artificial kidney and the extracorporeal circulation. Nevertheless, even though the anticoagulants are given continuously, clotting occurs within a few days making the continuous systems unusable. In addition, the complications and side-effects of chronic administration of heparin include bleeding, pruritus, allergy, osteoporosis, hyperlipidemia, and thrombocytopenia. Another problem is the finite life-span of the vascular access requiring repositioning of the access and sometimes resulting in loss of all suitable sites making it impossible to continue maintenance dialysis.
Peritoneal dialysis is another form of dialysis which can be used for ESRD patients. Peritoneal dialysis is performed by infusing a sterile, non-pyrogenic dialysis solution into the peritoneal cavity. Waste metabolites in the blood diffuse across the peritoneal membrane into the dialysate. The dialysate containing the waste products is removed immediately or after several hours, discarded and replaced with fresh dialysis solution.
Peritoneal dialysis offers several advantages over hemodialysis in that the patient's blood is not externalized, thereby eliminating the need for anticoagulants and access to blood vessels. However, the efficiency of peritoneal dialysis is low relative to hemodialysis. Also, currently available peritoneal dialysate contains lactate and has a low pH (5.0-5.5). A dialysate containing bicarbonate at a physiological pH (e.g., 7.4) would be preferable. But a stable solution of such composition cannot be produced because it would caramelize when heat sterilized.
The efficiency of peritoneal dialysis can be increased substantially by increasing the dialysate flow rate. This would require large volumes of expensive dialysis solution. Another disadvantage of current peritoneal dialysis practice is the loss of protein with the spent dialysate.
Kraus et al., U.S. Pat. No. 4,338,190, issued Jul. 6, 1982, attempted to eliminate both these disadvantages. To reduce the cost of the dialysate, they prepared the dialysate from concentrate and tap water purified by hyperfiltration. Such a system would require high pressures which may not be safe as a wearable artificial kidney. In addition, the system must be attached to a source of tap water. To eliminate protein loss, they separated the protein from the spent dialysate by means of a membrane having a low permeability to high molecular weight protein and a high permeability to low molecular weight toxic metabolites and return the protein to the patient. However, in this process of dialysate reclamation, no method or provision is made for removal of protein-bound toxins and undesirable proteins, if present.
Currently, there is no dialytic treatment which caters to the removal of protein-bound toxins in renal failure patients. In in vitro tests, Stange et al. (1993) Artif. Organs 17:809-812 demonstrated that by treating a hemodialysis membrane with albumin and adding albumin to the dialysate, protein-bound toxins in human plasma could be dialyzed. In salicylate over-dosed patients (without renal failure) treated with acute peritoneal dialysis, Etteldorf et al. (1961) J. Pediatr. 58:226 reported increased salicylate clearance when albumin is added to the peritoneal dialysate. There has been no attempt to incorporate the removal of protein-bound uremic toxins as a part of the strategy in the dialytic treatment of patients with renal failure, either on an acute or chronic basis. Commercially-available albumin is expensive, may cause allergic and other sensitivity complications, can carry infectious agents and would not be expected to remove uremic toxins bound to proteins other than albumin.
Lewin et al. (1974) Trans. Amer. Soc. Artif. Int. Organs 20:130-133 and Gordon et al. (1976) Trans. Am. Soc. Artif. Int. Organs 22:599-603) attempted to reduce the cost of the large volume of dialysate and also to reduce the volume of solution carried by the patient by regenerating the spent dialysate using a sorbent system. However, they subsequently found that the protein in the spent peritoneal dialysate interfered with the operation of the sorbent system. For a review article, see Roberts (1993) ASAIO J. 39:19-23.
The feasibility of constructing a wearable system has been demonstrated in that small disposable devices have been developed for handling biological samples and conducting certain clinical procedures. Shoji et al. (1988) Sensors Actuators 15:101-107) reported the use of a miniature blood gas analyzer fabricated on a silicon wafer. CIBA Corning Diagnostics Corp. (USA) has manufactured a microprocessor-controlled laser photometer for detecting blood clotting. Micromachining technology has enabled the manufacture of microengineered devices having structural elements with minimal dimensions ranging from tens of microns (the dimensions of biological cells) to nanometers (the dimensions of some biological macromolecule).